It has recently been discovered that nitric oxide mediates a number of physiological processes. It serves as a signal transduction mechanism in the central nervous system, is intimately involved with the regulation of blood pressure, and is produced by activated inflammatory cells thereby playing a role in pathological inflammatory conditions.
Garthwaite et al. and Stevens reported that stimulation of the glutamate site of the NMDA receptor complex leads to the release of nitric oxide. The nitric oxide stimulates the guanylate cyclase present in the CNS which in turns leads to an increase in cyclic GMP levels. A great deal of attention has been focused upon these excitatory amino acid receptors because it is believed that they are associated with learning and development. It is also believed that over-stimulation of these receptors is associated with a number of disease states such as, for example, epilepsy, stroke, and neurodegenerative diseases such as senile dementia, etc. Nature, 336, pages 308-309 and 385-388 (November 1988).
Knowles et al. reported the mechanism by which the nitric oxide is formed. An enzymatic reaction occurs in which L-arginine is converted into nitric oxide and citrulline. Knowles et al. also reported that the presence of N-monomethyl-L-arginine inhibited this enzymatic transformation. Proc. Natl. Acad Sci. USA, 86, pages 5159-5161 (July 1989).
Moncada et al. provided a review of the information which had been published to date regarding the physiological role of nitric oxide. Moncada et al. described the work of Knowles and Garthwaite regarding the role of nitric oxide in the CNS and postulated that nitric oxide is involved in seizures and other disease states associated with excessive excitatory neurotransmission. Biochemical Pharmacology, 38, No. 11, pages 1709-1715, (1989).
Moncada et al. reported that nitric oxide is associated with the regulation of blood pressure. These authors reported that an enzymatic pathway exists in the vasculature by which L-arginine is converted into nitric oxide. Nature, 333, pages 664-666 (1988). The nitric oxide relaxes the smooth muscles of the vasculature, producing dilation of these vessels which results in a lowering of blood pressure. Inhibition of nitric oxide synthesis by the administration of N-monomethyl-L-arginine produces a marked rise in blood pressure in test animals. Proc. Natl. Acad. Sci, USA, 86, pages 3375-3378 (1989).
Moncada et al. also reviewed earlier literature which reported that nitric oxide can be produced in large amounts by macrophages and polymorphonuclear leucocytes (PMN) and is associated with the effector functions of the cells. N-monomethyl-L-arginine inhibits the synthesis of nitric oxide by these cells.
The discovery of compounds capable of inhibiting the biosynthesis of nitric oxide would provide a new treatment for a number of disease states. They could be utilized in the treatment of conditions associated with low blood pressure such as, for example, shock. They could also be used to treat conditions caused by over-activity of the NMDA receptor complex such as epilepsy, stroke, neurodegenerative diseases, etc. They could also be used to treat conditions associated with excessive production of nitric oxide by macrophages and polymorphonuclear leucocytes such as arthritis, cirrhosis, transplant rejections, etc.